Gastrointestinal endoscopy is a diagnostic and therapeutic procedure which involves visual examination of different portions of the gastrointestinal tract using a long flexible tube known as an endoscope. An endoscope has a lens on one end and an eyepiece or video display system at the opposite end. Endoscopy is performed in moderately sedated patients by inserting the endoscope through the mouth or rectum and positioning the lens in the desired area of observation. Because the gastrointestinal tract is actively contracting during the procedure, the attending physician's visualization of certain regions of the GI tract is impaired or limited. In addition, this natural peristaltic reflex renders difficult the biopsy of certain areas of the GI tract and often interferes with the removal of polyps. In the case of attempted polyp removal, the procedure is made more difficult since the colon may be contracting when the polyps are being snared, cauterized and removed. The esophagus also moves at inopportune times such as when dilated veins known as varices are being injected.
Attempts to reduce gastrointestinal contractions in endoscopic procedures have involved the use of several different agents over the years. In particular, atropine and glucagon have been employed as premedications for this purpose.
Atropine is a belladonna alkaloid with competitive antimuscarinic actions. In the gastrointestinal tract it is an inhibitor of oral secretion and gastrointestinal motility. However, it is known by practitioners in the field to be only marginally effective as a paralytic agent for use in endoscopic procedures. In fact, controlled studies have failed to demonstrate any beneficial effects of atropine during endoscopies with regard to improvement in patient tolerance or facilitation of endoscopy (Ross, W., Gastrointestinal Endoscopy, Vol. 35, No 2, 120-126, 1989). Atropine is also associated with undersirable side effects such as blurred vision, headache, and urinary retention (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 5th Ed., MacMillan, New York, 1975 pp. 514-532) and an increased risk of cardiac arrhymthias (Ross, W., Gastrointestinal Endoscopy, Vol. 35, No. 2, 120-126, 1989). Consequently, atropine is rarely used as a premedication in endoscopy today.
Glucagon has been demonstrated to cause a variable reduction in gastroduodenal motility. The effect of glucagon appears to be dose-dependent with a minimally effective dose being 0.5 mg. However, glucagon does not facilitate colonoscopic evaluation (Norfleet, R. G., Gastrointestinal Endoscopy, Vol. 24, 164-5, 1978). In addition, it has been shown that even at doses as high as 2 mg, glucagon does not reduce contractions in the antrum (Gregerson et al., Scan. J. Gastroenterol. 23 (Supp 152) 42-47, 1988).
Glucagon administered intravenously at a dose of 1 mg followed by 2 mg IV over a period of 2 hours does affect, however, antroduodenal activity. That is, the cycle length and time between contractile activity in the duodenum is significantly increased while the mean pressure period is decreased (Larsen et al., Scan. J. Gastroenterol. Vol 21, 634-640, 1986).
Nausea and vomiting are two side effects associated with the use of glucagon. They are dose dependent, and can appear at a dose of 1 mg (Larsen et al., Scand. J. Gastroenterol. 21:634-640, 1986; Gregersen et al., Scand. J. Gastroent. 23 (Supp 152):42-47, 1988; Diamant Handbook Experimental Parm, Lefevre ed., Vol. 66/2:611-643, 1983). Since dosages required to sufficiently reduce motility frequently exceed 1 mg, side effects from glucagon use are prevalent. Such side effects render the patient extremely uncomfortable and often cause the endoscopic procedure to be interrupted or aborted.
Glucagon is used with a certain amount of success to facilitate barium examinations of the upper and lower GI tract by causing a dilation of the stomach and small bowel (Kreen, L., Br. J. Radiol., 48, 691-703, 1975). In addition, because of its effect on duodenal motility, glucagon has found use in endoscopic retrograde cholangiopancreatography (ERCP) to decrease contractions prior to cannulation of the ampulla of Vater.
Because of low efficacy and negative side effects, neither atropine nor glucagon have gained widespread use as gastrointestinal motility inhibitors. As a result, most upper and lower endoscopic examinations are performed without the benefit of halted peristalsis. Active peristalsis may prolong the procedure and leave the patient uncomfortable and the endoscopic procedure difficult and unpredictable. Thus the need for a safe, effective gastrointestinal paralytic agent with little or no side effects is great.
VIP is a 28 amino acid polypeptide hormone (Said, S., Mutt, V., Eur. J Biochem 28:199, 1972). It was first isolated in 1969 from normal hog lung and was shown at that time to cause a gradual but prolonged peripheral vasodilation. The polypeptide was given the name vasoactive intestinal peptide (VIP) in 1970 when it was isolated from porcine intestine (Said, S. I., Mutt, V., Science 169:1217, 1970). Since then, it has been isolated and its amino acid sequence determined in rat, pig, cow, guinea pig and human. Interestingly, the amino acid sequence of VIP isolated from all sources is identical except in guinea pig, where it differs by four non-polar amino acid substitutions. The amino acid sequence of human VIP has been published (Bunnett et al., Clin. Endocrinol. Metab. 59:1133-1137; 1984), and is shown in Table 1.
TABLE 1 ______________________________________ Amino Acid Sequence of VIP ______________________________________ 1 10 His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr- 11 20 Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys- 21 Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH.sub.2 ______________________________________
VIP immunoreactive neurons and nerve fibers have been found throughout the central nervous system and are widely distributed in many organ systems such as the genitourinary, gastrointestinal, respiratory, and cardiovascular systems (Khalil, et al., `Vasoactive Intestinal Peptide` in Gastrointestinal Endocrinology, Ed. J. C. Thompson, McGraw Hill, New York (1987) pp 260-272. Gastrointestinal motility is responsible for the orderly movement of secretions and nutrients through discrete anatomic portions of the gastrointestinal tract. An extensive neural and hormonal system regulates this complex mixing and propulsive activity. Neurotransmitters released by gastrointestinal neurons and hormones found in the circulation and enterochromaffin cells are the chemical messengers responsible for coordinating gastrointestinal function.
The action of these messengers on target cells may be contradictory. The circuitry of the enteric nervous system is such that an agent may stimulate a target cell and at the same time stimulate the release of another agent that inhibits the target cell. Thus, the action of an agent on the intact system cannot be predicted by the action on the individual cell. This has been found to be especially true when the data from various in vitro studies using isolated muscle strips exposed to different agents are compared to results seen in the clinical endoscopic setting.
For example, in rat and guinea pig isolated midcolon sections, atropine strongly inhibits ascending contractions at all grades of stretch but has no effect on descending relaxation (Grider and Makhlouf, Amer. J. Physiol. Soc. 25:G40-G45, 1986). Similarly, in isolated human ileum, atropine shows a primary relaxation in response to electrical field stimulation at all frequencies tested (Maggi et al., Naunyn-Schmiedeberg's Arch Pharmacol, 341:256-261, 1990). As previously discussed, however, atropine offers minimal if any beneficial effects in reducing gastrointestinal motility in the endoscopic setting.
The action of VIP on in vitro gastrointestinal motility is dependant on the experimental model, species, location within the gastrointestinal tract, and muscle layer examined. Several in vitro animal studies have suggested that VIP is responsible for relaxation of rat stomach and colon, guinea-pig stomach and gallbladder, chick rectum and rectal cecum, and human intestine (Grider and Makhlouf, Am. J. Physiol., 25:G40-G45, 1986; Grider, et al., Am. J. Physiol., G73-G78, 1985; Grider, J., Gastroenterology, 97: 1414-9, 1989; Said, et al., U.S. Pat. No. 3,880,826, 1975).
Several other studies in human, rabbit, guinea pig and mouse gastrointestinal tract suggest that VIP either has no effect or actually stimulates contractions in the gastrointestinal tract. For example, in distal human colon, VIP caused a small relaxation in circular muscle but did not relax longitudinal muscle contractions (Burleigh, D. E., Dig. Dis. Sci, Vol. 35, No. 5:617-621, 1990).
Additionally, in guinea pig and rabbit small intestine, cat duodenum, and mouse colon, VIP stimulated contractions of the layers of smooth muscle. In opossum duodenum, VIP stimulated contractions while glucagon stimulated relaxation (Anuras et al. Am. J. Physiol. 234:E60-E63, 1978; Cohen and Schwab Landry, Life sciences, Vol. 26, 816-822, 1990; Fontaine, et. al., Br. J. Pharmac., 89:599-602, 1986; Said et al., U.S. Pat. No. 3,880826, 1975; Gordon et al., Arch. int. Pharmacodyn. 305, 14-24, 1990).